Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation

Jevnikar, Zala; Östling, Jörgen; Ax, Elisabeth; Calvén, Jenny; Thörn, Kristofer; Israelsson, Elisabeth; Öberg, Lisa; Singhania, Akul; Lau, Laurie C.K.; Wilson, Susan J.; Ward, Jonathan; Chauhan, Anoop; Sousa, Ana R.; Meulder, Bertrand De; Loza, Matthew; Baribaud, Frédéric; Sterk, Peter J.; Chung, Kian Fan; Sun, Kai; Guo, Yike; Adcock, Ian M.; Payne, Debbie; Dahlén, Barbro; Chanez, Pascal; Shaw, Dominick; Krug, Norbert; Hohlfeld, Jens M.; Sandström, Thomas; Djukanović, Ratko; James, Anna; Hinks, Timothy S C; Howarth, Peter H.; Vaarala, Outi; Geest, Marleen van; Olsson, Henric

doi:10.1016/j.jaci.2018.05.026

Cited by 155 publications

(94 citation statements)

References 64 publications

(75 reference statements)

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“…1 Allergic asthma is typically a type 2 (T2) immune-mediated condition characterized by IL-4, IL-5, and IL-13 production from CD4 1 T H 2 cells and innate lymphoid cells, eosinophilic airway inflammation, and increased circulating IgE levels. 3 However, non-T2 cytokines have also been implicated in asthma pathogenesis, including IL-17A, 4,5 IL-6, 6 and IFN-g. [7][8][9] IFN-g and IFN-g-inducible type 1 (T1) immune gene expression is increased in the airways of a proportion of patients with severe asthma, [7][8][9][10] and IFN-g drives corticosteroid-refractory airway hyperresponsiveness (AHR) in a murine severe asthma model. 9 Importantly, patients with T1-high asthma coexpress T2 gene signatures to varying extents, 8 suggesting that interplay between distinct T H cell phenotypes might contribute to asthma pathology.…”

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confidence: 99%

A T cell–myeloid IL-10 axis regulates pathogenic IFN-γ–dependent immunity in a mouse model of type 2–low asthma

Branchett

Stölting

Oliver

et al. 2020

Journal of Allergy and Clinical Immunology

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confidence: 99%

A T cell–myeloid IL-10 axis regulates pathogenic IFN-γ–dependent immunity in a mouse model of type 2–low asthma

Branchett

Stölting

Oliver

et al. 2020

Journal of Allergy and Clinical Immunology

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“…Toll‐like receptor pathway genes were upregulated in bronchial brushings of these subjects, whereas expression of cell junction genes was reduced. Sputum sIL‐6R and IL‐6 levels correlated with sputum markers of remodelling and innate immune activation, in particular YKL‐40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL‐8 and IL‐1β . In addition, a group of patients with high IL6R mRNA level and high IL‐6 protein sputum levels associated with higher sputum neutrophil counts regardless of eosinophilic inflammation status has been identified in the same cohort, with poor lung function and higher levels of systemic IL‐6 and CRP .…”

Section: Non‐t2 Il‐6‐associated Clustersmentioning

confidence: 69%

Precision medicine for the discovery of treatable mechanisms in severe asthma

Chung

Adcock

2019

Allergy

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Although the complex disease of asthma has been defined as being heterogeneous, the extent of its endophenotypes remains unclear. The pharmacological approach to initiating treatment has, until recently, been based on disease control and severity.The introduction of antibody therapies targeting the Type 2 inflammation pathway for patients with severe asthma has resulted in the recognition of an allergic and an eosinophilic phenotype, which are not mutually exclusive. Concomitantly, molecular phenotyping based on a transcriptomic analysis of bronchial epithelial and sputum cells has identified a Type 2 high inflammation cluster characterized by eosinophilia and recurrent exacerbations, as well as Type 2 low clusters linked with IL-6 trans-signalling, interferon pathways, inflammasome activation and mitochondrial oxidative phosphorylation pathways. Systems biology approaches are establishing the links between these pathways or mechanisms, and clinical and physiologic features.Validation of these pathways contributes to defining endotypes and treatable mechanisms. Precision medicine approaches are necessary to link treatable mechanisms with treatable traits and biomarkers derived from clinical, physiologic and inflammatory features of clinical phenotypes. The deep molecular phenotyping of airway samples along with noninvasive biomarkers linked to bioinformatic and machine learning techniques will enable the rapid detection of molecular mechanisms that transgresses beyond the concept of treatable traits. K E Y W O R D Seosinophilic asthma, precision medicine, severe asthma, systems biology

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“…A new study reports the importance of epithelial IL-6 trans-signalling, in the absence of systemic inflammation, as a new asthma phenotype with frequent exacerbations, blood eosinophilia and increased airway inflammation with infiltration of T cells and macrophages [41].…”

Section: Anti-inflammatory Profile and Mode Of Action Of 18-cineolementioning

confidence: 99%

New Perspectives for Mucolytic, Anti-inflammatory and Adjunctive Therapy with 1,8-Cineole in COPD and Asthma: Review on the New Therapeutic Approach

2020

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The mucolytic monoterpene 1,8-cineole (eucalyptol), the major constituent of eucalyptus species, is well known for its anti-inflammatory, antioxidant, bronchodilatory, antiviral and antimicrobial effects. The main protective antiviral, anti-inflammatory and mucolytic mechanisms of 1,8-cineole are the induction of interferon regulatory factor 3 (IRF3), the control of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB) along with decreasing mucin genes (MUC2, MUC19). In normal human monocytes direct inhibition was shown of reactive oxygen species (ROS)-mediated mucus hypersecretion and of steroid resistence inducing superoxides (O 2 Á-) and pro-inflammatory hydrogen peroxides (H 2 O 2) with partial Digital Features To view digital features for this article go to

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Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation

Abstract: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.

Cited by 155 publications

References 64 publications

A T cell–myeloid IL-10 axis regulates pathogenic IFN-γ–dependent immunity in a mouse model of type 2–low asthma

A T cell–myeloid IL-10 axis regulates pathogenic IFN-γ–dependent immunity in a mouse model of type 2–low asthma

Precision medicine for the discovery of treatable mechanisms in severe asthma

New Perspectives for Mucolytic, Anti-inflammatory and Adjunctive Therapy with 1,8-Cineole in COPD and Asthma: Review on the New Therapeutic Approach

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